Malignant hyperthermia is a pharmacogenetic disease in man and pigs which predisposes to a catastrophic, often fatal syndrome during general anesthesia. Skeletal muscle of affected man and pigs is characterized by abnormal in vitro metabolic and contracture responses to certain anesthetic agents. The abnormal contracture and metabolic responses of malignant hyperthermia-susceptible (MHS) muscle could be caused by sustained increased levels of myoplasmic free calcium. We propose to investigate for a lesion of membranes which function to regulate free calcium concentration of the muscle cell. Experiments which have demonstrated aberrations in MHS pig muscle contractility and in calcium binding by isolated muscle membranes will be applied to isolated preparations from MHS humans. Pharmacologic agents with differential agonistic and antagonistic effects on in vitro muscle contraction will be used to determine the mechanism (e.g., excitation-contraction coupling, sarcoplasmic reticulum/calcium uptake and release) which must remain intact for the abnormal response of MHS muscle to occur. Using biochemical investigations of membranes isolated from control and MHS muscle we will explore a pharmacogenetic lesion of MHS muscle membranes which function to regulate free myoplasmic calcium concentration. A comparison of the effects of temperature perturbations and pharmacologic agents on contracture of muscle fibres and on calcium binding by isolated membranes will provide a basis for regulating a membrane lesion to abnormal contraction of MHS affected muscle. The information obtained will provide a basis for understanding the pathogenesis, form a diagnostic base, and give rationale for prevention and/or treatment of malignant hyperthermia during general anesthesia.